Role of catecholamines and cyclic AMP systems in phencyclidine and morphine dependence. Study of mutant mice

To investigate an involvement of catecholamines and/or the cyclic adenosine monophosphate (cAMP) systems in the development of drug dependence, we examined whether phencyclidine (PCP) and morphine dependence were developed in tyrosine hydroxylase (TH) heterozygous (TH^+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP^+/-) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days) and increased the level of cAMP in the striatum, but not in the thalamus/hypothalamus. In TH^+/- and CBP^+/- mice, however, we could not find PCP-induced place preference. The increased level of cAMP in the striatum was observed in CBP^+/-, but not TH^+/- mice. When wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased jumping, rearing, and forepaw tremor counts as a sign of withdrawal and an increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. In TH^+/- and CBP^+/- mice, however, jumping and forepaw tremor counts were decreased compared to in wild-type mice. An increase in the level of cAMP in the thalamus/hypothalamus in CBP^+/-, but not in TH^+/- mice was observed. These results suggest that catecholamines and CBP are involved in the development of PCP and morphine dependence, and that changes in catecholaminergic and/or cAMP systems induced by repeated PCP and morphine treatments play an important role in the addiction to PCP and morphine.